Several years of leukemia research has led the principal investigator to a hypothesis that many cancers remain hormone-dependent, retain the ability to terminally differentiate, and exhibit many normal cell properties. The present study was initiated to exploit one of these properties, namely hormone sensitivity of leukemia cells, in an effort to develop a lineage specific, gentle, safe and effective drug which will destroy leukemia cells. In particular, a drug will be devised which will specifically bind erythropoietin, and in so doing will competitively inhibit growth of erythroleukemia cells which require this hormone for their survival and proliferation. The drug will be composed of the soluble exoplasmic domain of the Epo receptor (solEpoR) which will be expressed and purified through recombinant DNA technology. In phase l, we have shown the feasibility of this project. In particular, we have initiated the synthesis of the human solEpoR, expressed EpoR in bacterial, baculovirus and mammalian systems, demonstrated that solEpoR binds Epo, and most importantly we have determined that solEpoR has the ability to kill Epo- dependent cells. In Phase Il we will scale up production of solEpoR and attempt to prove the efficacy of soluble Epo receptors in inhibiting growth of Epo-dependent leukemias in animal models. In addition we will compare the ability of various mutated EpoRs to inhibit growth of Epo dependent cells to determine which is the best candidate to use as an anti-hormone drug. We believe that this soluble receptor approach to cancer treatment can be generalized to any hormone dependent malignancy. Therefore, we also wish to test this approach using other cytokine receptors which are required for the proliferation of myeloid and lymphoid tumors and perhaps other cancers. PROPOSED COMMERCIAL APPLICATION: Product: A modified cytokine receptor which has been proven to have selective toxicity to cells of a certain hemopoietic lineage. This new form of drug should prove useful in fighting specific cancers or altering specific pathways of differentiation in the body which may be producing hyperplasia.